6, 8-(methylenedioxy)-2, 4-octadienoic acid and its alkyl esters



United States Patent 2,992,234 6,8-(METHYLENEDIOXYyZA OCTADIENOIC ACIDAND ITS ALKYL ESTERS Donald S. Acker, Wilmington, Del., assignor to I.

du Pont de Nemours and Company, Wilmington, Del., a corporationof'Delaware No Drawing. Continuation of application Ser. No. 560,062,Jan. 19, 1956. This application June 16, 1959, Ser. No. 820,571

Claims. (Cl. 260-340.7)

This invention is concerned with a new route to cz-Iipoic acid and thechemical intermediates involved.

This application is a continuation of my allowed copending US.application Serial No. 560,062 filed =1 anuary 19, 1956, now abandoned.

Lipoic acid is a member of the B vitamin group which is involved in thebiochemical decarboxylation of a-keto acids. In this role it has beenshown to be an essential metabolite for a number of microorganisms. Itis also a usefulchemotherapeutic agent in the treatment of liver disease(Rausch, Arzneimittelforsch. 5, 32-4 (1955)), and has a beneficialeflect on chick growth (De Busk and Williams, Arch. Biochem. Biophys.55, 587 (1955)).

The known natural sources of lipoic acid do not represent practicalstarting materials for the preparation of a-lipoic acid because of lowyields and the complicated procedures required for isolation. Thealternative of chemical synthesis has been explored to some extent, andseveral synthetic routes have been demonstrated. However, all of theseroutes involve intermediates which are expensive to obtain or prepare.

This invention has as an. object the provision of a new synthetic routeto lipoic acid. Another object is the preparation of intermediates forlipoic acid. Other objects will appear hereinafter.

These objects are accomplished by the present inven tion of6,8-(methylenedioxy)e2,4-octadienoic acid and its esters, preferablyalkyl esters, and their preparation by the acid-catalyzed reaction offormaldehyde with 2,4, 6-heptatrienoic acid and its esters.

Lipoic acid is prepared from 2,4,6-heptatrienoic acid and itis esters byreaction of formaldehyde therewith to form6,8-(methylenedioxy)-2,4-octadienoic acid (or an ester thereof),hydrogenation to the corresponding 6,,8(methylenedioxy)-octanoic acid(or an ester thereof), alcoholysis of the same with an alcohol and anacid catalyst to the alkyl 6,8-dihydroxyoctanoate which upon reactionsuccessively with thionyl chloride and an. alkali metal disulfide isconverted to an alkyl lipoate which on hydrolysis with aqueous caustic,followed by acidification, yields lipoic acid.

The particular advantage of 6,8-'(methylenedioxy)- 2,4-octadienoic acidand its alkyl esters as intermediates to lipoic acid is that the2,4,6-heptatrienoic acid and its alkyl. esters from which they areprepared according to this invention are readily synthesized fromacetylene and alkyl acrylates as shown by Kalb and Sauer, U.S-.2,540,736..

6,8-(methylenedioxy)-2,4-octadienoic acid and its alkyl esters are alsouseful as polymerizable dienes. They are converted by heat and/or apolymerization catalyst to thermoplastic solid polymers which on furthertreatment with crosslinking agents or vulcanization accelerators areconverted to insoluble, infusible crosslinked polymers. When a mixtureof the thermoplastic form of the polymer with a crosslinking agent iscoated from melt or solution on a metal surface and crosslinking is thenbrought about by baking, a durable enamel coating on the metal isobtained.

The following examples in which parts are by weight are illustrative ofthe invention.

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EXAMPLE I Methyl 6,8-(merhylenedi0xy)-2,4-octadienoate O HC=OH(CH=OH)z-( +2CHaO A mixture of 55 parts of purified dioxane, 8-parts of concentrated sulfuric acid, and 6 parts of paraformaldehyde isstirred and cooled to 0 C., and 13.8 parts of methyl2,4,6-heptatrienoate is added slowly. The mixture is stirred at roomtemperature for 40 hours, diluted with parts of ice water, and extractedwith three 100-part portions of ether. Fractionation of the driedsolution affords 4.5 parts of methyl 6,8-(methylenedioxy)-2,4-octadienoate, B.P. 108-115 C. (0.7 mm); n 1.5180. The lightabsorption spectrum of an ethanol solution of this compound shows amaximum at 257 millimicrons (molecular extinction coefficient 23,000).

Analysis.Calculated for C H O C, 60.59%; H, 7.12%. Found: C, 60.14%; H,7.34%.

The distillation residue from the fractionation noted above is a viscousmelt containing polymerized methyl 6,8-(methylenedioxy)-2,4-octadienoate which sets to a solid polymer oncooling.

EXAMPLE II Methyl 6,8-(methylenedi0xy -0ctan0ate A mixture of 4.3 partsof methyl 6,8-(methylenedioxy)-2,4-octadienoate, 0.5 part of 10%palladiumon-carbon hydrogenation catalyst and 65 parts of hexane isplaced in a hydrogenation apparatus and hydrogenated at 35-20 p.s.i.pressure until no more hydrogen is absorbed. The catalyst is filtered,the solvent is distilled, and the product fractionated yielding 3.8parts of methyl- 6,8-(methy1enedioxy)-octanoate, B.P. 78 (0.1 mm), n1.4508-1.4518.

Analysis.--Calculated for C H O C, 59.41%; H, 8.91%. Found: C, 59.24%;H, 9.00%.

EXAMPLE III 6,8-(methylenedioxy)-2,4-0ctadienoic acid A mixture of 30parts of paraformaldehyde, 200 parts of dioxane and 37 parts ofconcentrated sulfuric acid is cooled to 0 C. and 57.4 parts of2,4,6-heptatrienoic acid is added. The mixture is stirred at roomtemperature for 48 hours and then diluted with 200 parts of ice water.The resulting mixture is extracted with three 225-part portions ofchloroform. The chloroform extracts are combined, dried over magnesiumsulfate, and distilled to remove the solvent. There remains a residue ofcrude 6,8-(methylenedioxy)-2,4-octadienoic acid in the form of a viscousoil. This residue is dissolved in 160 parts of methanol and hydrogenatedin the manner of Example I I, using 1 part of 10% palladium-on-carboncatalyst. Both esteri-fication (methanol) and reduction take place inthis step. The product comprises 36.8 parts (39% yield) of methyl6,8-(methylenedioxy)-octanoate.

Analysis.Calculated for C H O C, 59.41%; H, 8.91%. Found: C, 59.90%; H,9.11%.

EXAMPLE IV Methyl 6,8- methy lenedioxy octarwate A mixture of 19.5 partspanaformaldehyde, parts dioxane and 25 parts concentrated sulfuric acidis cooled to 0 C., and 44.0 pants of methyl 2,4,6-heptatrienoate isadded. The mixture is stirred at room temperature for 42 hours, and 300parts of ice water is added. The organic layer is separated, and thewater layer is extracted with three 100-part portions of ether. Theether extract and organic layer are combined and dried, and the ether isdistilled. The residue is diluted with 200 parts of 50%methanol-cyclohexane and hydrogenated over one part ofpalladium-on-carbon catalyst. The catalyst is filtered, and the residuedistilled yielding 30.7 parts of methyl 6,8-(methylenedioxy)-octanoate,B.P. 95 (0.47 mm.)-102 (0.27 mm), n 1.44901.4489.

Methyl 6,8-(methylenedioxy)-octanoate is heated in methanol in thepresence of a small amount of sulfuric acid. Methylal is given off, andheating is continued for several hours until no more methylal distills01f. The residue is dissolved in benzene and treated with thionylchrolide in the presence of pyridine. The mixture is then quenched inice and the organic material is taken up in benzene and distilled toyield a yellow oil.

The yellow oil is refluxed in an ethanol solution of sodium disulfideuntil it is converted to methyl lipoate. The resulting mixture is thenheated with aqueous caustic until saponified. Acidification of themixture yields free lipoic acid which is separated by extraction withbenzene and purified by distillation, followed by recrystallization fromcyclohexane. It is identified as lipoic acid by assay for pyruvateoxidation factor by the general method of Gunsalus, Dolin and Struglia,J. Biol. Chem. 194, 849 (1952).

The reaction with formaldehyde is generically applicable to2,4,6-heptatrienoic acid and esters, preferably alkyl esters thereof,i.e., to compounds of the formula wherein n is a cardinal numeral, e.g.,up to 18 or more preferably not greater than 4. By substituting otheralkyl 2,4,6-heptatrienoates (i.e., the ethyl, propyl, t-butyl, octadecyl, etc., esters) for methyl 2,4,6-heptatrienoate in Example I, thecorresponding alkyl 6,8-(methylenedioxy)- 2,4-octadienoates are obtainedon reaction with formaldehyde, Aryl and alicylic esters can also beemployed, e.g., phenyl, naphthyl, and cyclohexyl 2,4,6-heptatrienoatescan be used. The reaction is applicable to any 2,4,6-heptatrienoic acidesters of a monohydroxy hydrocarbon which is aliphatically saturated,i.e., free from nonaromatic unsaturation.

In carrying out the reaction of 2,4,6-heptatrienoic compounds withformaldehyde, it is preferred to employ at least two moles offormaldehyde for each mole of the trienoic compound. The formaldehydemay be introduced as such (i.e., as gaseous monomeric formaldehyde) oras any of the condensed forms of formaldehyde, such as paraformaldehydeor trioxane, which release free formaldehyde under the acidic conditionsof carrying out the reaction.

Acidic materials in general catalyze the reaction of 2,4,6-heptatrienoiccompounds with formaldehyde. Hydrochloric acid, zinc chloride, boronfluoride/water complexes, phosphoric acid and the like may be employed.However, mineral acids are preferred, particularly sulfuric acid,because its use is accompanied by a minimum of side reactions. Organicacids may also be used. For example, methyl 2,4,6-heptabrienoate may behydrolyzed in aqueous sodium hydroxide and the resulting 2,4,6-heptatrienoic acid isolated by acidifying the mixture with hydrochloricacid, taking up the organic material in ben- 4 zene and evaporating thebenzene layer. The free acid (melting point 901 00 C.) is dissolved indioxane, and an excess of gaseous monomeric formaldehyde is bubbled intothe solution to yield a dioxane solution of6,8-methylenedioxy-2,4-octadienoic acid. The acid serves as a catalystfor the reaction. The free 6,8-(methylenedioxy)- 2,4-octadien0ic acid isobtained by evaporation of the dioxane.

As indicated above, the use of an organic solvent in the process ofpreparing 6,8-(methylenedioxy) 2,4,-octadienoic acid and its estersaccording to this invention is not essential. However, the use of asolvent permits better control of the rate of reaction and therefore ispreferred. Suitable solvents include the saturated hydrocarbons, such asbenzene, pentane, cyclohexane and the like; halogenated hydrocarbons,such as chloroform, tetrachloroethane, chlorobenzene and the like; andethers, such as diethyl ether, tetrahydrofuran, dioxane and the like.

Temperature is not a critical factor in the process of this invention,and 2,4,6-heptatiienoic acid and its esters will react with formaldehydeto form 6,8-(methylenedioxy)-2,4-octadienoic acid and its esters over awide 1 range of temperatures above and below room temperature.

However, for practical purposes, and to minimize side reactions, it ispreferred to carry out the reaction in the temperature range of 050 C.,and particularly in-the range of 0-25 C. Pressure may be varied aboveand below atmospheric pressure during this reaction. When gaseousmonomeric formaldehyde is employed, it is sometimes desirable to useelevated pressure. Otherwise there is no advantage to operating atpressures other than atmospheric pressure. I

The foregoing detailed description has been given for clearness ofunderstanding only and no unnecessary limitations are to be understoodtherefrom. The invention is not limited to the exact details shown anddescribed for obvious modifications will occur to those skilled in theart.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. Methylenedioxyoctadienoic compounds of the formula 4 wherein n is acardinal number of 0 to 18, inclusive.

2. A 6,8-(methylenedioxy)-2,4-octadienoic acid ester of a monohydroxyhydrocarbon of 1l8 carbons which is aliphatically saturated.

3. 6,8-(methylenedioxy)-2,4-octadienoic acid.

4. Process for the preparation of 6,8-(methylened-ioxy) 2,4-octadienoicacid and alkyl 6,8-(methylenedioxy)-2,4- octadienoates whereinformaldehyde is reacted at a temperature of 0-50" C. and under acidicconditions with a compound of the formula wherein n is a cardinal numberof 0 to 18, inclusive, the formaldehyde and said compound being in theratio of at least two moles of formaldehyde per mole of triene.

5.. Process wherein a member of the group consisting of2,4,6-heptatrienoic acid and esters thereof with monohydroxyhydrocarbons of 118 carbons free of nonaromatic unsaturation is reactedwith formaldehyde at from 0-5 0 C. under acidic conditions.

No references cited.

1. METHYLENEDIOXYOCTADIENOIC COMPOUNDS OF THE FORMULA